Gamma-herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8), Epstein-Barr virus (EBV), and murine herpesvirus 68 (MHV68) can establish lifelong persistent infection in host with latent infection and are associated with the development of lymphomas and other cancers. Both latency and lytic replication play important roles in viral transmission and tumor development. Thus, it is crucial t understand the fundamental mechanisms regulating the balance between latency and lytic replication. Recently, it has been shown that oxidative stress due to excessive levels of reactive oxygen species induces KSHV reactivation. Therefore the hypothesis is that KSHV senses and utilizes the oxidative stress response network, to regulate virus life cycle. Since reactive oxygen species have a wide range of roles in both physiological and pathological settings, the long-term objective is to better understand the roles host regulators of the cellular redox balance in the control of KSHV life cycle, and to develop new therapeutic approaches, with the following specific aims: Aim I. To identify cellular factors and network regulating KSHV reactivation induced by oxidative stress using a combination of traditional cell biology approaches and new mathematic approaches. The activation of cellular signaling molecules will be quantitatively measured using Phospho-Flow technique. Aim II. To determine the role of oxidative stress related pathways in regulating virus life cycle in vivo using MHV-68 as a model system and whether reduction of oxidative stress can inhibit tumor growth in vivo using a transplant model. Whether the antioxidant N-acetyl-cysteine (NAC) can be used as a chemoprevention strategy or a combination of anti-oxidant and rapamycin might be a more effective treatment will be assessed. Also whether NAC can enhance or reduce the therapeutic efficacy of the commonly used chemotherapy drug doxorubicin will be evaluated. Achieving the above aims will define the molecular mechanism by which the KSHV senses cell stress signals to decide the switch between latency and lytic replication. It not only addresses a fundamental biological question, but also can facilitate the development of new preventive and/or therapeutic approaches.